The medicinal aspects of the aryl-acetic acids and their 2-methyl analogues, especially the 2-(R,S)-aryl-propionic acids, have been reviewed by Shen (Shen T. Y., in: Wolff, M. F. (ed), Burger's Medicinal Chemistry, 4th edition, part III, Wiley, Interscience, New York, pp 1205-1271). Numerous clinical studies continue to demonstrate the efficacy of this particular class of compounds against pain and inflammation. It has been shown that some carboxylic acids of this class of compounds process mechanisms of inhibition on the cyclo-oxygenase pathway as well as actions not typical for the cyclo-oxygenase pathway (e.g. see Carty, Th., J., et al. in: Annual Reports in Medicinal Chemistry, Vol. 23, pp 181-189, 1988; Academic Press). For the 2-aryl-propionic acids a stereoselective disposition kinetic has been established, and also an unidirectional metabolic chiral inversion of the less active R-enantiomer to the more active S-isomer (Adams, S., et al., 1976, J. Pharm. Pharmacol. 28, 256; Hutt A. J., and Caldwell, J. Clin. Pharmac., 9, 371, 1984; Hutt, A. J., and Caldwell, J., J. Pharm. Pharmacol., 35, 693, 1983). Moreover, new studies have revealed that intravenous injection of racemic ibuprofen inhibits the neutrophil dependent edema response of rabbit skin to C5a ala-arg in addition to PGE.sub.2, an observation suggesting a non-cyclo-oxygenase action of this derivative of the 2-aryl-propionic acid class (M. Ramport and T. J. Williams, Biochem., Pharmakol, 35, 581, 1986).
Although numerous studies continue to demonstrate the efficacy of this class of 2-arylpropionic acids against pain and inflammation, some studies have also shown that some carboxylic acids of non-steroidal anti-inflammatory drugs possess mechanism of action beyond their classical cyclo-oxygenase pathway inhibition. Furthermore, salicylate which is the major metabolite of aspirin has been observed to be effective in blocking rat paw edema induced by platelet activating factor (PAF) which is believed an activity not shared by other non-steroidal anti-inflammatory drugs. (R. S. Cordeiro, P. M. Silva, M. A. Martins, and B. B. Vorgaflig, Prostaglandin, 32, 719, 1985).
Therefore, the pure S-enantiomers seem to be appropriate for a number of reasons for therapeutic use: e.g., i) a reduction in the dose of the biologically active S-enantiomer with respect to the racemate; ii) substance administration is considerably less than in comparison to the (R,S)-racemic mixture; hence less side effects are most likely to be expected, and iii) the drug action is faster since the receptors are enantiospecific having a high intrinsic affinity for these particular enantiomeric compounds.
Therefore, it is desirable to be able to produce the S-enantiomer on an industrial scale in order to produce economically attractive yields of these S-(+)-enantiomers, having a high optical purity (98%) by applying stereospecific chemical synthesis. Apart from obtaining pure enantiomers of 2-aryl-alkanoic acids, especially 2-aryl-propionic acids, using optically active bases (see Blaschke, G., Angew Chem. 92, 14-25, 1980), or through biochemical racemate separation (P. Lesti and P. Piccardi, Eur. Patent. Appln. EP 195,717, 1986; J. S. Nicholson and J. G. Tantum, U.S. Pat. No. 4,209,638, 1980), only a few chemical stereoselective processes have been disclosed. Also enzymes, especially from pig liver, have been used for racemic separation (Marshek, W. J. and Miyano, M., 1973, Biochim. Biophys. Acta 316, 363).
Furthermore, it has been reported by Cambon and Klibanov (B. Cambon and A. M. Klibanov, Appl. Biochem. and Biotechnology, 9, 255-258, 1984) that a lipase-catalyzed production of optically active acids can be prepared via asymmetric hydrolysis of esters. Specifically, it has been found that lipase from Candida cylindracea hydrolyses octyl R(+) but not S-(-)-2-chloropropionate. See also similar methods which are disclosed in the following references:
Marshek, W. J. and Miyano, M. (1973), Biochim. Biophys. Acta 316, 363.
Oritani, T. and Ymashita, K. (1974), Agric. Biol. Chem. 38, 1965.
Yamaguchi, Y., Oritani, T., Tajima, N., Komatsu, A. and Moroe, T. (1976), J. Aqric. Chem. Soc. Japan 50, 475.
McGahren, We. J., Sax, K. J., Kunstmann, M. P. and Ellestad, G. A. (1977), J. Org. Chem. 42, 1659.
Mori, K. and Akao, H. (1980), Tetrahedron 36, 91.
Iriuchijima, S. and Keiyu, A. (1981), Agric. Biol. Chem. 45, 1389.
Kawai, K., Imuta, M. and Ziffer, H. (1981), Tetrahedron Lett., 22, 2527.
Iriuchijima, S. and Kojima, T. (1982), Agric. Biol. Chem. 46, 1153.
Lavayre, J., Verrier, J. and Baratti, J. (1982), Biotechnol. Bioeng. 24, 2175.
Iriuchijima, S., Keiyu, A. and Kojima, N. (1982), Agric. Biol. Chem. 46, 1593.
The usefulness and industrial application of these methods is restricted by the drawback that only a few of the many lipases exhibit stereospecifity in the hydrolysis of esters.
All of these techniques and biotechnological processes suffer from similar drawbacks at the present time. These processes are inefficient since they require large volumes of material for the recovery and racemization of the desired optical stereoisomer for chemical racemate separation and require redistillation of the solvents used. Finally, after the procedure is completed, only low yields of crystalline compounds of high optical purity are obtained from the mother liquors. Thus, the present invention, by eliminating all these unnecessary steps, will result in substantial savings in material costs, manufacturing, labor and equipment.
Methods for synthesizing racemic 2-aryl-alkanoic acids, especially 2-aryl-propionic acids and in particular (R,S)-ibuprofen, are well known and disclosed in several patents and the scientific literature, e.g. Tanonaka, T., et al., DE 3523082 Al, (1986), who uses microorganisms; JP-PSEN 40-7491 (1965); 47-18105, (1972); JP-OS 50-4040, (1975); DE 2404159 (1974); DE 1443429 (1968) by J. S. Nicholson and S. S. Adams; DE 2614306 by Bruzzese, T., et al., (1976); DE 2605650 by Gay, A., (1976); DE 2545154 by Heusser, J., (1976); and DE 2404160 by Kogure, K., et al., (1974).
Surprisingly, only a few methods for a stereospecific chemical synthesis for 2-aryl-alkanoic acids, especially 2-aryl-propionic acids, are known. Piccolo et al. (J. Org. Chem. 50, 3945-3946, 1985) describe a stereospecific synthesis by the alkylation of benzene or isobutylbenzene with (S)-methyl-2-(chlorosulfonyl)-oxy or 2-(mesyloxy) propionate in the presence of aluminum chloride yielding (S)-methyl-2-phenyl-propionate in good chemical yield (50-80%) and excellent optical yield of &gt;97% as determined by rotation through inversion of configuration at the attacking carbon atoms. The reaction conditions are very similar as described in some patents (Jpn. Kokai Tokkyo Koho 5808045; Chem. Abstracts, 1983, 98; 143138 k; Jpn. Kokai Tokkyo Koho 7979246; Chem. Abstracts, 1980, 92, 6253 f) where racemic reagents have been used. Extensions of this type of reactions to other aromatic substrates, e.g. toluene, isobutylbenzene, tetraline, anisole, naphthalene, 2-methoxy-naphthalene are described in Jpn. Kokai Tokkyo Koho 7971932; Chem. Abstracts 1979, 91, 20125 b; Jpn. Kokai Tokkyo Koho 78128327; Chem. Abstracts 1978, 89, 23975 y; Jpn. Kokai Tokkyo Koho 81145241; Chem. Abstracts 1982, 96, 68650 z; Jpn. Kokai Tokkyo Koho 78149945; Chem. Abstracts 1979, 90, 168303 h; Jpn. Kokai Tokkyo Koho 7844537; Chem. Abstracts 1978, 89, 108693 h; Jpn. Kokai Tokkyo 77131551; Chem. Abstracts 1978, 88, 104920 h. In a recent paper Piccolo et al. (J. Org. Chem. 52. 10, 1987) describe a synthesis leading to R-(-) ibuprofen, whereas Tsuchihashi et al. (Eur. Pat. Appl. EP 67,698, (1982); Chem. Abstracts 98, 178945 y, (1983) report a stereospecific synthesis of the R-(-) ibuprofen-methylester with excellent yields of about 75.0% and high optical purity (&gt;95%) in contrast to Piccolo et al. (J. Org. Chem. 32, 10, 1987) having an optical purity of 15% only for the R-(-) ibuprofen. However, the same authors have reported chemical yields of 68% of S (+) ibuprofen having an optical purity of 75-78%, only. Hayashi, et al. (J. Org. Chem. 48, 2195, 1983; in: Asymmetric Reactions and Processes In Chemistry; eds E. L. Eliel and S. Otsuka, ACS-Symposium Ser. 1985, 1982, 177) describe a stereospecific synthesis of S-(+) ibuprofen through asymmetric Grignard cross-coupling which are catalyzed by chiral phosphine-nickel and phosphine-palladium complexes. The enantiomeric excess of the coupling products with various alkenyl halides under the influence of the above-mentioned metal phosphine complexes, including amino acids, depends strongly on the ligand and ranges up to 94% with enantiomeric excesses in the 60-70% range. A very useful ligand has been found in chiral 2-aminoalkyl phosphines achieving reasonable chemical yields and high optical purity. Furthermore, optically active 2-aryl-alkonates have been synthesized via a Friedel-Crafts synthesis by Sato and Murai (Jpn. Kokai Tokkyo Koho JP 61,210,049 t 86,210,049, 1986) yielding 46% S-(+) ibuprofen. Giordano et al. (EP application 0 158 913, 1985) have reported a process for the preparation of optically active 2-aryl-alkanoic acids and intermediates thereof by halogenation on the aliphatic carbon atom to the ketal group and rearrangements of the haloketals yielding pharmacologically active 2-aryl-alkanoic acids. A stereochemical synthesis of 2-aryl-propionic acids is described by Robertson et al. (EP application 0 205 215 A2, 1986) using 2-(R.sub.1)-alkane as the carbon source for the fungi Cordyceps in particular for Cordiceps militaris, yielding enantiomeric S-(+) products of high optical purity.
Methods for the synthesis of anti-inflammatory 2- aryl-propionic acids are listed in the review by Rieu et al. (J. P. Rieu, A. Boucherle, H. Coussee and G. Mouzin, Tetrahedron Report No. 205, 4095-4131, 1986), also. However, this report is mostly concerned with the racemates rather than an evaluation of stereospecific chemical synthesis of 2-aryl-propionic acids.
In addition a new report on the stereochemical synthesis of 2-aryl-propionic acids for pure S- or R-enantiomers is disclosed in Kontakte (Darmstadt, 3, 13-15, 1989) as well as in a very recent paper by Lassen et al. (R. D. Lassen, E. G. Corley, P. Davis, P. J. Reider and E. J. J. Grabowski, J. Amer. Chem. Soc. 111, 7650, 1989)
The advances in catalytic asymmetric reactions applying transition metal complexes, i.e., the direct conversion of 1-aryl-ethane-halides of the R or S conformation with sodium tetracarboxyl-ferrate (-II) (Na.sub.2 Fe(CO).sub.4) in the presence of triphenylphosphine (Ph.sub.3 P), has made it possible to synthesize chiral compounds with high enantiomer excess and economical good yields (for review see, i.e., Ojima, I., Llos., N., Barton, C., Tetrahedron 1989, 45, 6091). Very recently it was possible to demonstrate that stoichiometric amounts of certain chiral materials can be very effectively applied as chiral materials in the presence of molecular sieves to obtain the desired chiral compound from a prochiral unsymmetrical ketone.
The present invention relates to a process of preparing a compound is stereospecific form of the formula: ##STR1## or pharmaceutically acceptable salts thereof wherein
Ar is a monocyclic, polycyclic or orthocondensed polycyclic aromatic group having up to 12 carbons in the aromatic ring which may be substituted or unsubstituted in the aromatic ring which comprises
(a) reacting (4S,5S)-2-alkyl-4-alkoxy-5-phenyloxazoline with a Group I metal containing base wherein the phenyloxazoline has the formula ##STR2## wherein R' is lower alkyl;
R'" is alkyl containing 1-10 carbon atoms;
Ph is phenyl or phenyl substituted with lower alkyl PA1 non-polar, no ability to solvate cations or anions, e.g. alkanes, benzenes, CH.sub.2 Cl.sub.2, CHCl.sub.3 ; PA1 weakly polar, can solvate cations, e.g. ether, THF, DME, di-tri, -tetra-glymes, pyridine, aliphatic tertiary amine; PA1 polar aprotic solvents, having good cation solvating capabilities, however with no ability to directly solvate anions, e.g. hexamethyl phosphoric triamide (HMPT), DMSO, DMF, Me.sub.2 CO, CH.sub.3 CN PA1 polar protic solvents which can be solvate both anions (hydrogen bonding) and cations, e.g. H.sub.2 O, NH.sub.3, CH.sub.3 OH, C.sub.2 H.sub.2 OH
(b) reacting the product of (a) with Ar-Hal, wherein Ar is as defined hereinabove and Hal is halide.